Ghrelin is produced by the stomach and hypothalamic neurons and it is an endogenous ligand for the growth hormone secretagogue receptor. Recently, ghrelin has also been found to regulate food intake and energy expenditure through an apparent hypothalamic mode of action. We discovered that ghrelin is present in a subset of hypothalamic neurons. Our preliminary studies also showed direct connectivity between the hypothalamic ghrelin network and arcuate nucleus neuropeptide Y (NPY)- and agouti related peptide (AGRP)-containing cells and POMC neurons and parvocellular thyrotropin releasing hormone (TRH)- and corticotropin releasing hormone (CRF)-producing neurons. We also revealed a direct presynaptic association between ghrelin and GABA axon terminals using electron microscopy and electrophysiology. Our observations, together with other available data on ghrelin's hypothalamic effects raised the intriguing possibility that ghrelin is a neuromodulator regulating the signaling flow in the hypothalamus to underlie normal daily energy homeostasis. In testing this hypothesis, the following specific aims will be addressed in mice: 1) Determine the interaction of ghrelin with key hypothalamic peptidergic systems that are involved in energy homeostasis. 2) Reveal ghrelin's effect on food intake, energy expenditure, electrophysiological properties and neuropeptide expression patterns of hypothalamic neurons in mice strains with altered metabolic functions. 3) Assess the effects of metabolic alterations on the expression levels of ghrelin and its receptor in the hypothalamus, stomach and blood. The execution of these studies using a multidisciplinary approach will shed light on a novel hypothalamic mechanism that may prove to be critical for the control of obesity and related disorders, including diabetes mellitus